Antiplatelet Therapy in Patients With Abdominal Aortic Aneurysm Without Symptomatic Atherosclerotic Disease

Key Points Question Do patients with abdominal aortic aneurysms without symptomatic atherosclerosis benefit from antiplatelet therapy? Findings In this comparative effectiveness research study using target trial emulation methods including 6344 patients with 131 047 trial cases, limited effectiveness of antiplatelets to lower the risk of ischemic events was noted. The absolute risk differences between the treatment groups were minimal. Meaning The results of this study suggest limited clinical relevance of treatment and warrant caution in prescribing prophylactic antiplatelet therapy for patients with abdominal aortic aneurysms without symptomatic atherosclerosis.


eMethods. Specifications of target trial protocol
A target trial was specified with the following components (resumé in eTable 1) Eligibility criteria.Enrollment of patients with a diagnosis of AAA, aged ≥50 and ≤ 90 years between January 2010 and August 2021, who had no manifestations of symptomatic peripheral arterial disease (PAD); intermittent claudication, rest pain, ischemic ulcers and gangrene, ischemic heart disease (IHD); angina, previous myocardial infarction (MI), manifestations of chronic myocardial ischemia, or ischemic stroke.Participants must not have any contraindications for antiplatelet therapy (major liver-or kidney impairment within the last 5 years of inclusion, recent major bleeding, or prevalent anticoagulant (OAC) treatment (within 6 months of inclusion), and no history of cancer (except non-melanoma skin-cancer) within 5 years from inclusion.Participants must not have used antiplatelet therapy (including ticagrelor and prasugrel) within the last 12 months prior to inclusion.
Baseline was defined as the first month of randomization when all eligibility criteria were met.
Treatment strategies.1. Usual medical care or 2. Initiation of antiplatelet therapy (aspirin or clopidogrel, type of antiplatelet at the discretion of the physician).When clinically warranted during the follow-up, patients and their physicians will decide whether to start, stop or switch therapy.
Treatment assignment.Each eligible participant will be randomly assigned to a strategy with initiation of treatment within 1 month from randomization.Patients with events of interest within this period will be excluded.Patients will be aware of the strategy to which they are assigned.
Outcomes.Outcomes of interest is a composite of MI and ischemic stroke.Secondary outcome is MI and ischemic stroke as separate outcomes as well as major bleeding, defined as any bleeding requiring hospital contact.
Follow-up.All participants will be followed from baseline and until first ischemic stroke, MI, death, loss to follow-up, or administrative end of follow-up (five years or august 2021), whichever happens first.
Causal contrasts.The intention-to-treat (ITT) effect of being assigned to antiplatelet therapy versus no initiation of antiplatelet therapy at baseline and the On-treatment (OT) effect of antiplatelet initiation and continuation over follow-up.

Statistical analysis.
In both ITT and OT analyses, we will use pooled logistic regression analysis to estimate the effect of antiplatelet therapy via comparison of 5-year risk of outcome expressed as hazard ratios and standardized survival curves. 1 For ITT analyses we fitted a pooled logistic regression with an indicator for of assigned strategy and a flexible function of months since randomization.For OT analyses we fitted a model after censoring participants if and when they deviate from assigned treatment.Time-varying stabilized inverse-probability weights will be used to adjust for time-varying confounding associated with adherence and outcome of interest.
To identify potential subgroups for whom treatment may potentially be more beneficial, stratified analyses will be conducted based on baseline information on age (>= 80 years), with and without concomitant statin therapy and according to type of antiplatelet (aspirin/ clopidogrel).

Target trial specification Target trial emulation Eligibility criteria
Diagnosis of AAA, age ≥ 50 years and ≤ 90 years, no previous symptomatic PAD, IHD, CVD, no use of antiplatelet therapy a , no contraindications for antiplatelet therapy b , no prevalent cancer c Baseline defined as day of randomization.

Same as target trial
Baseline defined as the first of every trial month where all eligibility criteria were met, yielding potentially 140 sequential trial months for each participant.

eMethods.
Specifications of Target Trial Protocol eTable 1. Protocol Components of Target Trial and Trial Emulation eTable 2. Definition of Variables eTable 3. Number of Individuals, Trial Cases and Outcome Events Included in Analyses eTable 4. Baseline Characteristics of the Study Population Before IPTW eTable 5. Intention-to-Treat Estimates of Outcomes (Ischemic and Bleeding Events) in Subgroups eTable 6. Sensitivity Analyses With Estimates of Outcomes (Ischemic and Bleeding Events) eFigure 1. Directed Acyclic Graph of Potential Confounding Factors eFigure 2. Flowchart of Inclusion eFigure 3. Plot of Maximum Standardized Difference of Baseline Covariates of Study-Population Before and After Applying IPTW This supplementary material has been provided by the authors to give readers additional information about their work.

Baseline characteristics of the study population before IPTW
© 2023 Nicolajsen CW et al.JAMA Network Open.eTable 5.

Intention-to-treat estimates of outcomes (ischemic and bleeding events) in subgroups
© 2023 Nicolajsen CW et al.JAMA Network Open.eTable 6.

Sensitivity analyses with estimates of outcomes (ischemic and bleeding events)
CI-Confidence Interval, DD-Daily Dose, a Intention-to-treat analyses, b On-Treatment analyses © 2023 Nicolajsen CW et al.JAMA Network Open.eFigure 1.

Directed Acyclic Graph of potential confounding factors Common
causes with association to exposure and outcome: sex, age, calendar year of inclusion, time since abdominal aortic aneurysm diagnosis, relevant comorbidity (diabetes, hypertension, atrial fibrillation, heart failure) use of other cardioprotective medication (statin, antihypertensives)